Abiraterone acetate, chemically designated as (3β)-17-(3-pyridinyl)-androsta-5,16-dien-3-yl acetate of formula
is a prodrug which is converted in vivo to abiraterone, 17-(3-pyridyl)-androsta-5,16-dien-3β-ol.
Abiraterone is a potent inhibitor of human cytochrome P45017α, a potential target enzyme in the treatment of hormone-dependent prostatic carcinoma.
Abiraterone acetate is the active ingredient of the approved drug (Zytiga®) which is administered in a solid oral dosage form (250 mg tablet).
Zytiga® in combination with prednisone is indicated for the treatment of patients with metastatic castration resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
Literature reports several processes for the preparation of abiraterone or derivatives thereof.
Abiraterone was first described in patent application EP 0633893 (BTG International Ltd.) covering 16,17-ene-17-(3-pyridyl) steroids as a class of compounds useful in the treatment of androgen- and oestrogen-dependent disorders.
Particularly, in the specific experimental work, abiraterone acetate is prepared from dehydroepiandrosterone-3-acetate and, then, converted into abiraterone.
Chromatography is required to give the desired acetyl ester by elution with petroleum-diethyl ether and crystallization from hexane. Abiraterone is obtained by elution with toluene-diethyl ether and crystallization from toluene.
However, it has been observed that the overall yield of the process is low (around 48%) and chromatography appears to be the only tool able to provide a substantially pure product which is, then, crystallised from apolar solvents and, optionally, used in the downstream of the process.
EP 0721461 (BTG International Ltd.) describes an improved method for the preparation of (3β)-acyloxy-16,17-ene-17-(3-pyridyl) steroids; especially, the preferred compound (3β)-acetoxy-17-(3-pyridyl)-androsta-5,16-diene via acylation of (3β)-hydroxy derivative and crystallization from ethanol/water and, then, hexane is prepared.
However, the estimated overall yield starting from dehydroepiandrosterone is low (around 41%) and, mainly, a final purification by reverse phase chromatography is required.
WO 2006/021776 (BTG International Ltd.) describes novel salt forms of C2-C4 acyl esters of abiraterone or a derivative thereof and to a process for the preparation of abiraterone or a salt or derivative thereof. The preferred salt is abiraterone acetate methanesulfonate which is, preferably, recovered from methyl tert-butyl ether.
WO 2006/021777 (BTG International Ltd.) describes a process for the preparation of abiraterone or C2-C4 acyl esters of abiraterone or a derivative thereof.
Coupling as well as isolation steps to abiraterone acetate are carried out by following the teachings of the International application WO '776 above.
However, the estimated overall yield of the process starting from dehydroepiandrosterone 3-acetate is very low (around 32%) with a purity around 97%; isolation as, inter alia, the mesylate salt entails an additional neutralization and optionally crystallization step(s) with further loss in yield.
Furthermore, Chinese application CN 101768199 discloses abiraterone acetate polymorphs A, B, C and D; methods of preparing said polymorphs comprise re-crystallizing abiraterone acetate from different solvents such as ethanol-hexane or ethanol-water mixtures, ethyl acetate or acetone, isopropanol as well as acetonitrile.
Chinese application CN 102731605 provides for an abiraterone acetate purification method, said method comprises salification of crude abiraterone acetate with phosphoric acid to give a pale yellow crystal, i.e. abiraterone acetate phosphate, neutralization and further recrystallization from methanol yielding the acetate product.
Chinese application CN 102030798 provides for a purification method of abiraterone acetate. The method comprises reacting trifluoromethanesulfonic acid as a salt forming reagent with crude abiraterone acetate to obtain dry abiraterone acetate trifluoromethanesulfonic salt with a purity of over 97%; and performing a neutralization reaction with alkali in dichloromethane to give abiraterone acetate. Chinese application CN 102558275 discloses α-Type abiraterone acetate polymorph; the preparation method comprises dissolving abiraterone acetate in a solvent under heating condition to form a solution, filtering, cooling, crystallizing and drying; solvents used in the method are water, methanol, ethanol, isopropanol, isopropyl ether, acetonitrile, THF, ethyl acetate, chloroform, dichloromethane, toluene, hexane, acetone and mixtures thereof.
Chinese application CN 102321142 discloses abiraterone acetate crystalline form E; the preparation method comprises dissolving abiraterone acetate in a solvent, crystallizing under cooling or water addition and solid separation; solvents used in the method are methanol, ethanol, isopropanol, acetone, acetonitrile and/or THF.
Co-pending international patent application No. PCT/EP2012/069937 in the name of the same Applicant relates to a process for the preparation of 17-substituted steroids and, more particularly, to an improved method of synthesizing abiraterone or derivatives thereof in high yield and purity by means of a key 3β-formyloxy intermediate. Abiraterone is, eventually, crystallized from alcoholic solvents and, optionally, converted into its 3β-acetoxy ester in accordance with known techniques which is, in turn, crystallized preferably from a heptane/ethanol solution.